Nephrol Dial Transplant (2012) 27: 882–890
doi: 10.1093/ndt/gfr771
Advance Access publication 14 February 2012
Editorial Review
Genetic causes of focal segmental glomerulosclerosis: implications for
clinical practice
Ilse M. Rood, Jeroen K.J. Deegens and Jack F.M. Wetzels
Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Correspondence and off print requests to: Jack F.M. Wetzels; E-mail: J.Wetzels@nier.umcn.nl
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common
cause of steroid-resistant nephrotic syndrome in children
and adults. Although FSGS is considered a podocyte dis-
ease, the aetiology is diverse. In recent years, many inher-
itable genetic forms of FSGS have been described, caused
by mutations in proteins that are important for podocyte
function. In the present commentary, we review these
genetic causes of FSGS and describe their prevalence in
familial and sporadic FSGS. In routine clinical practice, the
decision to perform the costly DNA analysis should be
based on the assessment if the results affect the care of the
individual patient with respect to the evaluation of extra-
renal manifestations, treatment decisions, transplantation
and genetic counselling.
Keywords: adults; children; focal segmental glomerulosclerosis;
mutation analysis; steroid-resistant nephrotic syndrome
Introduction
Focal segmental glomerulosclerosis (FSGS) is a description
of histological lesions characterized by mesangial sclerosis,
obliteration of capillaries, hyalinosis, foam cells and adhe-
sion between the glomerular tuft and Bowman’s capsule [1].
In addition to the classical sclerotic lesions of FSGS, several
other histological variants have been described. A group of
renal pathologists redefined these histological variants and
proposed a standardized pathological classification system
for FSGS based entirely on light microscopic examination.
The classification, also known as the Columbia Classifica-
tion, defines five histological variants: the collapsing variant,
the tip variant, the cellular variant, the perihilar variant and
FSGS not otherwise specified [2]. In adult patients, FSGS is
one of the most common patterns of glomerular injury [3],
and over the last decades, the incidence of FSGS has in-
creased significantly in Afro-Americans as well as in Cau-
casians [4]. In USA, FSGS now represents 35% of the renal
biopsies performed in adults with a nephrotic syndrome [4].
Approximately 30–50% of adults with FSGS do not respond
to steroid therapy. In children, steroid resistance is the hall-
mark of FSGS since a renal biopsy is only taken in children
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with a nephrotic syndrome when treatment fails. In the large
majority of children with steroid-resistant nephrotic syn-
drome (SRNS), light microscopy shows FSGS (63–73%)
or related forms such as minimal change disease (0–15%),
diffuse mesangial sclerosis (3–15%) or IgM nephropathy
(3–15%) [5, 6]. In children, these causes of SRNS are re-
sponsible for 5–20% of all cases of end-stage renal disease
(ESRD) [7].
Injury to the podocytes plays a central role in the patho-
genesis of SRNS/FSGS [8]. However, the aetiology of
podocyte injury is quite diverse and includes B-cell and
T cell-dependant factors, infections, medication and mal-
adaptive responses that occur due to the loss of functioning
nephrons or hyperfiltration [9, 10]. In addition, SRNS/
FSGS can be caused by mutations in genes that encode
proteins that play key roles in maintaining podocyte ultra-
structure. This field of research started with the discovery
that mutations in the podocytic protein nephrin were
responsible for the congenital nephrotic syndrome (CNS)
of the Finnish type [11]. Since then, many new genetic
causes of SRNS/FSGS have been identified, the latest
being the identification of mutations in MYO1E as cause
of autosomal recessive SRNS [12].
The discovery of these genetic causes of SRNS/FSGS
has underlined the role of the podocyte in SRNS/FSGS
and helped to unravel the biology of podocyte function.
However, it is unclear how to incorporate all this new in-
formation in clinical practice. This review will provide an
overview of genetic causes of SRNS/FSGS. Specifically,
we address the questions when and why genetic testing
should be considered and discuss its implications.
Genetic causes of SRNS/FSGS
Table 1 lists the genes and their related proteins that cause
non-syndromic SRNS/FSGS. These proteins are mainly
expressed in the podocyte and are involved either directly
or indirectly in the organization of the slit diaphragm and
the actin cytoskeleton. FSGS caused by mutations in neph-
rin, podocin, CD2AP, PLCe1 and MYO1E is characterized
by an autosomal recessive pattern of inheritance. As a rule,
onset of disease is in childhood (Table 1). In contrast,
Nephrol Dial Transplant (2012): Editorial Review
a
Table 1. Genetic causes of non-syndromal SRNS/FSGS
Gene Gene product Inheritance
NPHS1 [11, 13] Nephrin AR
NPHS2 [13, 14] Podocin AR
PLCe1/NPHS3 [15] PLCe1 AR
CD2AP [16] CD2-associated protein AR
MYO1E [12] Non-muscle Myosin-1E AR
TRPC6 [17] TRPC6 AD
ACTN4 [18] Alpha-actinin-4 AD
INF2 [19] Formin AD
a
Includes FSGS-related histologic variants in children with SRNS (minimal change disease, diffuse mesangial sclerosis, IgM nephropathy). DMS, diffuse
mesangial sclerosis.
mutations in a-actinin-4, TRPC6 and INF2 cause autoso-
mal dominant FSGS. In most patients, onset of disease is in
adulthood, and many patients do not develop a manifest
nephrotic syndrome.
FSGS can also be caused by mutations in genes that
encode proteins that are not only expressed in the podo-
cytes but also, or even more so, in other tissues and cell
types. In these syndromic forms of FSGS, the extrarenal
manifestations are most prominent and often diagnostic.
Examples are given in Table 2. Of note, in some of these
diseases, FSGS may be the only or the presenting manifes-
tation, thus mimicking isolated FSGS. Well-known exam-
ples are mutations in the transcription factor WT1 and
mitochondrial mutations (Table 2).
Prevalence of mutations in SRNS/FSGS
Currently, mutation analysis is expensive, and single genes
are analysed separately. Therefore, a cost-effective approach
requires information on the prevalence of causative muta-
tions in a given population.
Although there is a wealth of published data, it is not easy
to calculate true prevalence rates. Many authors present data
on cohorts with varying often overlapping patient groups
with different clinical characteristics. Often, mutation anal-
ysis for a certain gene is done in patients in whom mutations
in other known genes have been excluded. Thus, the real
prevalence will often be much lower than predicted from the
data. Lastly, most studies report the prevalence of mutations
in a single gene and few attention is given to the potential
role of combinations of heterozygous mutations in different
genes.
Table 3 provides a summary of the prevalence of different
genetic mutations in childhood and adult-onset SRNS/FSGS.
It is important to realize that the prevalence is dependant on
the family history, the age of the patients, the ethnicity and
the histologic lesion. The family history suggests an autoso-
mal dominant pattern of inheritance when there are diseased
persons in multiple generations. An autosomal recessive pat-
tern of inheritance is usually present when there are diseased
persons in only a single generation. Obviously, there are
some pitfalls. In autosomal recessive diseases, the first
affected child will be considered sporadic. In this respect,
an autosomal recessive inheritance should especially be
suspected in children with ‘sporadic’ FSGS born from
883
Remarks
Most common cause of Finnish type CNS
Most common cause of genetic forms of SRNS in childhood
Associated with DMS
Very rare. Role of heterozygous mutations unclear
TRPC-6 is a calcium channel; variable phenotypic expression within families.
Often non-nephrotic proteinuria; incomplete penetrance
Most common identified cause of adult familial FSGS; majority of patients
present with non-nephrotic proteinuria.
consanguineous parents. Autosomal dominant and recessive
inheritance may be unnoticed if there is incomplete pene-
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trance, with mutation carriers being unaffected. Mitochon-
drial mutations are typically characterized by maternal
inheritance. However, because these mutations often follow
a dominant inheritance pattern, a mutation in mitochondrial
DNA (mtDNA) may be overlooked.
Several conclusions can be drawn (Table 3): almost 100%
of patients with CNS have a mutation. In Finland, mutations
in nephrin are the rule (>95%), whereas in other populations
also mutations in other genes occur. Podocin mutations pre-
dominate in patients with infantile (4–12 months) and early
childhood (1–5 years) SRNS. For podocin, ethnicity is im-
portant. Mutations are most frequently reported in studies
that included patients from Western European countries. The
most frequent mutation, R138Q, is considered a European
founder mutation. Up to 16% of children will have a muta-
tion in WT1. A mutation should be considered in patients
with a female phenotype (important to assess genotype
if a mutation is found) or males with abnormal genital
development.
Most cases of adult-onset familial FSGS are inherited as
an autosomal dominant disease. The most common causa-
tive gene is INF2 (up to 17%), other mutations include
TRPC6 (up to 12%) and ACTN4 (3.5%). However, pene-
trance is often incomplete with variable expression. Many
adult patients with familial FSGS present with non-nephrotic
proteinuria.
Mutations in podocyte genes are rarely found in adults
with isolated sporadic FSGS, with the exception of com-
pound heterozygous NPHS2 mutations involving the com-
mon podocin R229Q polymorphism. The R229Q variant
is present in 1–2.5% of Afro-Americans and in 5–10%
of Caucasians [44, 50, 60–62]. There is no evidence that this
variant is pathogenic in its own [62]. However, a study by
Machuca et al. [48] suggests that FSGS develops in patients
who carry the R229Q variant in combination with one patho-
genic NPHS2 mutation. This study mainly included Western
European patients who developed nephrotic syndrome at a
later age (19 years) than patients who were homozygous or
compound heterozygous for pathogenic NPHS mutations.
Of note, in cohorts of patients with sporadic FSGS not living
in Western Europe, the prevalence of the combination of the
R229Q variant and a pathogenic NPHS2 mutation was much
lower, 0–2% [14, 44, 49].
 884
Table 2. Genetic causes of syndromal SRNS/FSGSa

Gene Gene product Inheritance Associated conditions Remarks

WT-1 [20–22] WT-1 AD Denysh–Drash syndrome: male pseudohermaphroditism, malignancies Presentation in childhood. Mutations occur in phenotypic
(Wilms’ tumour) and progressive glomerulopathy with nephrotic syndrome. females (may have XY genotype); or in phenotypic and
The glomerulopathy usually begins within the first months of life, with genotypic males with genital development disorders
progression to ESRD by the age of 3–4 years. Renal biopsy typically shows such as cryptorchism, hypospadia, testicular atrophy.
DMS. May present as isolated FSGS in adulthood.
Frasier syndrome: male pseudohermaphroditism, progressive
glomerulopathy, gonadoblastoma. Proteinuria begins in childhood (usually
2–6 years) with progression to ESRD during the second or third decade of
life. Histology typically discloses FSGS.

Mitochondrially tRNALeu(UUR) Maternal Most common A3243G mutation. May present with isolated FSGS
encoded tRNA Associated with MELAS syndrome (mitochondrial myopathy, encephalopathy, FSGS related to mitochondrial DNA mutations typically
leucine 1 [23] lactic acidosis and stroke-like episodes). Other manifestations: diabetes, develops in adulthood.
deafness, visual impairment, cardiomyopathy

LAMB2 [24] Laminin b2 AR Pierson’s syndrome (microcoria and other complex ocular abnormalities, Typically age of onset <1 year.
CNS, DMS)

ITGB4 [25] B4-integrin AR Epidermolysis bullosa

CD151 [26, 27] Tetraspanin AR Epidermolysis bullosa, sensorineural deafness, nail dystrophy The only available renal biopsy of one patient did not
show FSGS but thickening/fragmentation of the GBM.
CD151-null mice develop massive proteinuria with FSGS
SCARB [28] SCARB2/LIMP-2 AR Action myoclonus-renal failure syndrome (progressive myoclonic epilepsy Lysosomal membrane
associated with renal failure)

LMX1b [29] LIM HboxTF1 AD Nail-patella syndrome (hypoplastic or absent patella, dysplasia finger- Renal abnormalities do occur. Mostly limited to

Nephrol Dial Transplant (2012): Editorial Review

and toenails, and dysplasia of elbows and frequently glaucoma) micro-albuminuria
FSGS with overt proteinuria is rare.

Non-muscle myosin MYH9 AD Non-syndromic sensorineural deafness autosomal dominant type 17

IIA [30] Epstein syndrome
Alport syndrome with macrothrombocytopenia
Sebastian syndrome
Fechtner syndrome
Macrothrombocytopenia with progressive sensorineural deafness.
a
This table provides a limited list. We have excluded FSGS associated with other kidney diseases such as nephronophtisis or Alport’s syndrome. Other syndromic forms include FSGS associated with severe
malformations (mandibulo-acral dysplasia; Schimke immune-osseous dysplasia, Galloway-Mowat syndrome), glycosylation disorders and mitochondrial diseases. Genes: SMARCAL1 [31], GMS1 [32], PMM2
[33], ALG1 [34], ZMPSTE24 [35], LMNA [36], CoQ2 [37], CoQ6 [38], PDSS2 [39]. DMS, diffuse mesangial sclerosis; GBM, glomerular basement membrane.

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 Nephrol Dial Transplant (2012): Editorial Review
Table 3. Prevalence of mutations in SRNS/FSGSa

Age of onset

Adult FSGS
Genes CNS Infantile NS Childhood NS Adult FSGS (familial) (sporadic) Remarks

NPHS1 34–90% 0–2% [13, 40] 14% [42] n.a. 2% [42]

[11, 13, 40, 41]
NPHS2 0–51% 19–41% [13, 40] 0–18% 4–24% [48, 49] 0–11% In Western European adults, adult-onset FSGS is
[11, 13, 40, 43] [5, 44–47] [14, 44, 48, 49, 50] caused by combination of R229Q and one pathogenic
NPHS2 mutation.
R138Q is considered a founder mutation in Europe.
One study (US) suggested higher prevalence of R138Q in
patients versus controls (1.2 versus 0.2%) [14].
Studies show that allele frequency of R229Q is higher in
patients versus controls [49, 50].
LAMB2 3–9% [13, 40] 5% [13] n.a. n.a. n.a.

PLCe1 0–50% 0% (histology: 0% (histology: Prevalence dependent on family history and histology:
[15, 46, 51] FSGS) [52] FSGS) [52] Sporadic DMS 21%, familial DMS 50%, sporadic FSGS
0%; familial FSGS 12%.

In most studies patients with other mutations were

excluded first (e.g. NPHS1, NPHS2, WT1, LAMB2)
[15, 51]

MYO1E n.a. n.a. 0–4% [12] n.a. n.a. Study of Mele et al. excluded NPHS1, NPHS2 and WT1.
Up to 3.5% in familial cases of FSGS; 0% in DMS or
sporadic cases of FSGS.
CD2AP n.a. n.a. 0–11% [16, 46, 53, 54] 0% [41, 42] 0% [42] Role of heterozygosity discussed; Unaffected parents with
heterozygous mutation described by Lowik et al. and
Gigante et al. [46, 54]
WT1 0–16% 9–13% [13, 40] 0–13% [6, 45, 50, 55] n.a. 0% [50] WT1 mutations are found predominantly in phenotypic
[13, 40, 41] females or males with abnormal genital development.
ACTN4 n.a. n.a. 0% [46, 53] 3.5% [18] 0% [18, 50]
TRPC6 n.a. 5% [40] 0–6% [46, 56–58] 0–12% [17, 58] 0–2% [42, 56] Gigante et al. excluded mutations in NPHS1,NPHS2, WT1,
CD2AP and ACTN4.
Study from Heeringa et al. included patients with age of
onset 9–30 years [58]
INF2 n.a. n.a. n.a. 12–17% [19, 59] 1% [59] In the sporadic case in Boyer et al. parents were not studied.
a
Studies included with n > 10. DMS, diffuse mesangial sclerosis; NS, nephrotic syndrome; n.a., not available.

885
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886
Genetic screening in clinical practice
The discovery of genes associated with FSGS has greatly
increased our knowledge of podocyte biology and our in-
sight in the pathogenesis of FSGS. Obviously, these studies
must continue and be expanded to include well-defined
cohorts of patients with FSGS. This will not only allow
clinicians to detect new genes but also to describe in detail
phenotype–genotype correlations. Although the identifica-
tion of genetic mutations can be done relatively easily,
genetic testing is expensive and results can take weeks or
even months. Therefore, the relevance of genetic screening
for the individual patient must be carefully considered be-
fore advising these procedures in routine clinical practice.
Table 4 lists the relevant questions that should be asked
when considering genetic testing in a patient with FSGS.
These questions will be addressed below.
Genetic screening affects treatment decisions
Hinkes et al. [15] described a patient with a mutation in
PLCe1 who apparently responded to treatment with ste-
roids. However, this example is the exception to the rule,
and most studies have indicated that genetic forms of FSGS
are steroid resistant [42, 63]. It is likely, although not based
on firm evidence, that steroid-resistant patients also will not
respond to immunosuppressive therapy with alkylating
agents. Thus, the discovery of a mutation could benefit
the patient by avoiding exposure to prolonged treatment
with corticosteroids or cyclophosphamide. However, the
latest guidelines advise not to use alkylating agents in
any patient with SRNS or FSGS but rather to use cyclo-
sporine A (CsA) [64]. The efficacy of CsA is attributed to
its direct effect on the stabilization of the podocyte actin-
cytoskeleton [65]. Thus, we need to know if the presence of
a podocyte mutation decreases the efficacy of CsA. Some
studies indeed suggested that CsA may be less effective in
FSGS secondary to genetic mutations. Machuca et al. [48]
reported that only two out of 15 patients with SRNS devel-
oped a partial remission after CsA therapy. Duration or
intensity of therapy was not described. Buscher et al.
[40] retrospectively evaluated the response to treatment
with CsA in children with SRNS and reported a response
rate of 17% in patients with and 68% in patients without a
mutation. However, these conclusions are based on only 12
patients with a genetic mutation, and CsA was given for 6
months in a dose titrated to levels of only 80–120 ng/mL.
There are many case reports of patients who have re-
sponded to CsA. These studies included patients with a
mutation in podocin, MYO1E, TRPC6, WT1 and CoQ6
[12, 38, 43, 56, 57]. Based on the available data, results
Table 4. Genetic screening of patients with SRNS/FSGS: which
questions to ask.
1. Does the result of genetic screening influence your treatment decisions?
2. Does the result of genetic screening affect counselling for extra-renal
disease?
3. Does the result of genetic screening help in family counselling?
4. Does the result of screening affect decisions related to kidney
transplantation?
Nephrol Dial Transplant (2012): Editorial Review
of mutations analysis should not be used to discard CsA as
therapeutic agent. Mutation analysis will only affect treat-
ment decisions if, in a given patient, one considers pro-
longed steroid treatment and/or the use of an alkylating
agent.
Genetic screening affects care and counselling of
patients
Genetic testing might be important in those conditions where
the causative gene influences patient care and follow-up. The
most illustrative example is a mutation in WT1. If mutations
in the WT1 gene are found, one should investigate the gender
genotype of the female (thus excluding the XY genotype
with pseudohermaphroditism), and patients with a WT1
mutation should be screened for development of a Wilms’
tumour or gonadoblastoma. In patients with mitochondrial
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mutations, one may consider more thorough studies of ear
and vision and also regular check for diabetes. Obviously,
in syndromal forms of FSGS, additional studies may be
needed, guided by the underlying disease (Table 2).
Genetic screening affects counselling of the family
Genetic testing is important for genetic counselling. In
children with SRNS, the prevalence of a genetic cause of
the disease is high. Identification of a genetic mutation in a
child can help the parents in their decision to plan new
pregnancies. Also, the results can be used for prenatal ge-
netic testing. Lastly, if a brother or a sister of a patient, with
a known mutation that is associated with SRNS, develops a
nephrotic syndrome, the use of steroid treatment should be
questioned. The results of genetic tests can also be of help
when these children are grown up and begin planning a
family. In a patient with a homozygous or compound het-
erozygous pathogenic podocin mutation, the risk of disease
transmission is 50% in case they marry a partner who is a
carrier of the R229Q allele. In European countries, up to
10% of the people may have the R229Q variant. Mutations
in WT1 are also relevant. Not only is the risk of transmis-
sion high (autosomal dominant, 50% risk), the disease may
also be more serious in the offspring. If a woman with
isolated FSGS related to a WT1 mutation becomes preg-
nant, the children can develop the more severe Denysh–
Drash Syndrome or Frasier Syndrome.
Genetic testing should be considered in patients with
adult-onset FSGS, who are planning parenthood. Autoso-
mal dominant forms of FSGS will be readily identified by a
positive family history, although one must keep in mind the
large heterogeneity in phenotypic expression. Risk of trans-
mission is high and should be discussed. In adults with
sporadic FSGS, the relevance of genetic testing for genetic
counselling has been questioned since the prevalence of
finding a mutation is very low. There may be one excep-
tion, which involves the NPHS2 gene. As mentioned, in
Western Europeans, up to 10% of patients with adult-onset
FSGS may be compound heterozygous for one pathogenic
NPHS2 mutation and the R229Q variant [48]. Half of the
offspring thus will carry one pathogenic mutation, which
causes no disease. However, when combined with the
R229Q variant, these children are at high risk of developing
Nephrol Dial Transplant (2012): Editorial Review 887

late-onset FSGS. This is not hypothetical since the R229Q
variant is prevalent in the normal population (up to 10%). In
these cases testing the patients for the R229Q variant should
be sufficient.
Genetic screening and kidney transplantation
It is well known that in familial forms of FSGS, the like-
lihood of recurrent disease after kidney transplantation is
very low. In the era before the regular use of mutation
analysis, Conlon et al. [66] described the clinical character-
istics of 26 multigenerational families (probably autosomal
dominant inheritance) and 34 single generation families
(probably autosomal recessive) with FSGS. In 41 patients,
a kidney transplantation had been done. Only one patient
developed clinical and laboratory evidence of recurrent
FSGS (2.5%). In recent studies, similar conclusions were
reached. Machuca et al. reported no recurrence in 9 patients
with two podocin mutations and Jungraithmayr et al.
reported no recurrence in 11 patients with two podocin
mutations, whereas Weber et al. reported 1 patient with
recurrence out of 32 patients with two podocin mutations
[48, 67, 68]. Other studies have reported a higher inci-
dence of recurrence (up to 38%); however, these studies
have been criticized since most recurrences developed in
patients with only one mutation [69, 70]. Thus, in isolated

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Fig. 1. Diagnostic algorithm for mutation screening in children with SRNS. DMS ¼ diffuse mesangial sclerosis. This algorithm is suitable for patients
who are evaluated for SRNS. In clinical practice, the family history should be part of the initial analysis. If in a patient with a nephrotic syndrome the
family history is positive, genetic screening should be considered before starting steroid treatment. Note: in patients with SRNS, a renal biopsy should be
performed to exclude other histologies such as IgA nephropathy, Alport syndrome, Dense Deposit Disease, Membranoproliferative Glomerulonephritis.
Histologies compatible with FSGS include minimal change disease and IgM nephropathy.
888
cases of SRNS/FSGS, the detection of a homozygous or
compound heterozygous mutation will predict a low risk
of recurrence. Although it will not directly influence the
treatment of the patient, this knowledge should be reas-
suring for patients and their parents. Furthermore, it may
enhance the likelihood of living donor transplantation be-
cause a potential donor can be assured that the risk of graft
failure due to recurrence is low.
The low risk of recurrence does not hold for patients
with CNS due to NPHS1 mutations. In these patients, the
reported recurrence rate is 25% [71]. It is likely that pro-
teinuria is caused by the development of anti-nephrin anti-
bodies, as these antibodies were detected in almost half of
the patients [70].
In patients with a family history of SRNS/FSGS, knowl-
edge of the type of mutation will not be informative from
the patient’s perspective. However, mutation analysis may
be more important for selection of the donor. Winn et al.
[72] have reported two donors, who developed nephrotic
syndrome after donation. The first patient was a white fe-
male, who donated her kidney to her brother who was
known with FSGS. The donor remained healthy during
two pregnancies after donation. Seven years after donation,
Fig. 2. Diagnostic algorithm for mutation screening in adults with FSGS. Asterisk indicates that NPHS2 mutations can show a pseudo-autosomal
dominant pattern of inheritance, e.g. one parent with a homozygous mutation in NPHS2 and a parent with R229Q, the child carrying one pathogenic
mutation in combination with R229Q.
Nephrol Dial Transplant (2012): Editorial Review
she developed proteinuria due to FSGS with a nephrotic
syndrome and progressed to ESRD. The second patient was
a man, who donated his kidney to his brother. This in-
volved a multigenerational family with FSGS, with most
patients being non-nephrotic. Five years after donation,
proteinuria developed, and 7 years later, ESRD was noted.
Thus, in patients with FSGS and presumed autosomal
dominant inheritance, genetic testing is advised. If a muta-
tion is found, the donors should be analysed. Although hard
data are lacking, it seems wise to exclude donors with a
mutation from donating a kidney.
Guidelines for genetic screening in clinical practice
We advise genetic testing in all children with CNS since
mutation detection rate is 100%, starting with NPHS1.
Figures 1 and 2 illustrate the diagnostic algorithms for
children and adults with SRNS/FSGS. We suggest that
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mutation analysis be performed in children with familial
and sporadic SRNS. This advice is based on the fact that the
prevalence of genetic causes of SRNS is high, and the
results will often affect family counselling. We suggest
mutation analysis in adults with a family history of FSGS.
Nephrol Dial Transplant (2012): Editorial Review
This information can be used when discussing the pros-
pects of a living related donor transplantation and donor
selection. Genetic screening is of limited value in adult
patients with sporadic FSGS, with the exception of screen-
ing for the R229Q in young adults, who would like to be
informed of the risk that the disease develops in their off-
spring. The sequence of testing is dependant on the esti-
mated prevalence, the size of the gene, and the relevance of
the findings (see above).
Areas of uncertainty
Detailed genotype–phenotype correlations are lacking. No
study has addressed the relation between genotype and
histological classification. It is important to develop and
exploit large registries of patients with SRNS/FSGS with
extensive genetic screening and adequate follow-up. Only
such registries can provide information on treatability of
genetic FSGS, its outcome, etc.
Next generation sequencing could change our views. It is
to be expected that whole exome screening will be done in
the next years at very low costs; this will enable to analyse
all genes related to FSGS in one array; this also will help to
clarify genotype–phenotype relationships and explore the
role of bigenic or multigenic heterozygous mutations.
Conflict of interest statement. None declared.
References
1. Fahr T. Pathologische anatomie des morbus brightii. In: Henke F,
Lubarsch O (eds). Handbuch der Speziellen Pathologischen Anatomie
und Histologie. Vol. 6. Berlin, Springer, 1925, 156
2. D’Agati V, Fogo A, Bruijn J et al. Pathologic classification of focal
segmental glomerulosclerosis: a working proposal. Am J Kidney Dis
2004; 43: 368–382
3. Swaminathan S, Leung N, Lager DJ et al. Changing incidence of
glomerular disease in Olmsted County, Minnesota: a 30-year renal
biopsy study. Clin J Am Soc Nephrol 2006; 1: 483–487
4. Haas M, Meehan S, Karrison T et al. Changing etiologies of unex-
plained adult nephrotic syndrome: a comparison of renal biopsy find-
ings from 1976–1979 and 1995–1997. Am J Kidney Dis 1997; 30:
621–631
5. Gbadegesin R, Hinkes B, Vlangos C et al. Mutational analysis of
NPHS2 and WT1 in frequently relapsing and steroid-dependant neph-
rotic syndrome. Pediatr Nephrol 2007; 22: 509–513
6. Ruf RG, Schultheiss M, Lichtenberger A et al. Prevalence of
WT1 mutations in a large cohort of patients with steroid-resistant
and steroid-sensitive nephrotic syndrome. Kidney Int 2004; 66:
564–570
7. Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD
due to focal segmental glomerulosclerosis in the United States.
Am J Kidney Dis 2004; 44: 815–825
8. Kriz W, Hosser H, Hahnel B et al. Development of vascular pole
associated glomerulosclerosis in the Fawn-hooded rat. J Am Soc
Nephrol 1998; 9: 381–396
9. Deegens JK, Steenbergen EJ, Wetzels JF. Review on diagnosis and
treatment of focal segmental glomerulosclerosis. Neth J Med 2008;
66: 3–12
10. Deegens JK, Wetzels JF. Immunosuppressive treatment of focal seg-
mental glomerulosclerosis: lessons from a randomized controlled trial.
Kidney Int 2011; 80: 798–801
11. Kestila M, Lenkkeri U, Mannikko M et al. Positionally cloned gene
for a novel glomerular protein–nephrin–is mutated in congenital neph-
rotic syndrome. Mol Cell 1998; 1: 575–582
889
12. Mele C, Iatropoulos P, Donadelli R et al. MYO1E mutations and
childhood familial focal segmental glomerulosclerosis. N Engl J Med
2011; 365: 295–306
13. Hinkes BG, Mucha B, Vlangos CN et al. Nephrotic syndrome in
the first year of life: two thirds of cases are caused by mutations
in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 2007;
119: e907–e919
14. McKenzie LM, Hendrickson SL, Briggs WA et al. NPHS2 variation
in sporadic focal segmental glomerulosclerosis. J Am Soc Nephrol
2007; 18: 2987–2995
15. Hinkes B, Wiggins RC, Gbadegesin R et al. Positional cloning un-
covers mutations in PLCE1 responsible for a nephrotic syndrome
variant that may be reversible. Nat Genet 2006; 38: 1397–1405
16. Kim JM, Wu H, Green G et al. CD2-associated protein haploinsuffi-
ciency is linked to glomerular disease susceptibility. Science 2003;
300: 1298–1300
17. Reiser J, Polu KR, Moller CC et al. TRPC6 is a glomerular slit
diaphragm-associated channel required for normal renal function.
Nat Genet 2005; 37: 739–744
18. Weins A, Kenlan P, Herbert S et al. Mutational and biological anal-
Downloaded from http://ndt.oxfordjournals.org/ at University of Louisville on January 31, 2013
ysis of alpha-actinin-4 in focal segmental glomerulosclerosis. J Am
Soc Nephrol 2005; 16: 3694–3701
19. Brown EJ, Schlondorff JS, Becker DJ et al. Mutations in the formin
gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 2010;
42: 72–76
20. Barbaux S, Niaudet P, Gubler MC et al. Donor splice-site mutations in
WT1 are responsible for Frasier syndrome. Nat Genet 1997; 17:
467–470
21. Klamt B, Koziell A, Poulat F et al. Frasier syndrome is caused by
defective alternative splicing of WT1 leading to an altered ratio of
WT1 1/-KTS splice isoforms. Hum Mol Genet 1998; 7: 709–714
22. Drash A, Sherman F, Hartmann WH et al. A syndrome of pseudo-
hermaphroditism, Wilms’ tumor, hypertension, and degenerative
renal disease. J Pediatr 1970; 76: 585–593
23. Lowik MM, Hol FA, Steenbergen EJ et al. Mitochondrial tRNA-
Leu(UUR) mutation in a patient with steroid-resistant nephrotic
syndrome and focal segmental glomerulosclerosis. Nephrol Dial
Transplant 2005; 20: 336–341
24. Zenker M, Aigner T, Wendler O et al. Human laminin beta2
deficiency causes congenital nephrosis with mesangial sclerosis and
distinct eye abnormalities. Hum Mol Genet 2004; 13: 2625–2632
25. Kambham N, Tanji N, Seigle RL et al. Congenital focal segmental
glomerulosclerosis associated with beta4 integrin mutation and epi-
dermolysis bullosa. Am J Kidney Dis 2000; 36: 190–196
26. Karamatic CV, Burton N, Kagan A et al. CD151, the first member of
the tetraspanin (TM4) superfamily detected on erythrocytes, is essen-
tial for the correct assembly of human basement membranes in kidney
and skin. Blood 2004; 104: 2217–2223
27. Sachs N, Kreft M, van den Bergh Weerman MA et al. Kidney failure
in mice lacking the tetraspanin CD151. J Cell Biol 2006; 175: 33–39
28. Berkovic SF, Dibbens LM, Oshlack A et al. Array-based gene
discovery with three unrelated subjects shows SCARB2/LIMP-2
deficiency causes myoclonus epilepsy and glomerulosclerosis.
Am J Hum Genet 2008; 82: 673–684
29. Dreyer SD, Zhou G, Baldini A et al. Mutations in LMX1B cause
abnormal skeletal patterning and renal dysplasia in nail patella syn-
drome. Nat Genet 1998; 19: 47–50
30. Ghiggeri GM, Caridi G, Magrini U et al. Genetics, clinical and patho-
logical features of glomerulonephritis associated with mutations of
nonmuscle myosin IIA (Fechtner syndrome). Am J Kidney Dis
2003; 41: 95–104
31. Boerkoel CF, Takashima H, John J et al. Mutant chromatin remodel-
ing protein SMARCAL1 causes Schimke immuno-osseous dysplasia.
Nat Genet 2002; 30: 215–220
32. Sartelet H, Pietrement C, Noel LH et al. Collapsing glomerulopathy in
Galloway-Mowat syndrome: a case report and review of the literature.
Pathol Res Pract 2008; 204: 401–406
33. Sinha MD, Horsfield C, Komaromy D et al. Congenital disorders of
glycosylation: a rare cause of nephrotic syndrome. Nephrol Dial
Transplant 2009; 24: 2591–2594
890
34. Kranz C, Denecke J, Lehle L et al. Congenital disorder of glycosyla-
tion type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum
Genet 2004; 74: 545–551
35. Agarwal AK, Zhou XJ, Hall RK et al. Focal segmental glomerulo-
sclerosis in patients with mandibuloacral dysplasia owing to
ZMPSTE24 deficiency. J Investig Med 2006; 54: 208–213
36. Rankin J, Auer-Grumbach M, Bagg W et al. Extreme phenotypic
diversity and nonpenetrance in families with the LMNA gene muta-
tion R644C. Am J Med Genet A 2008; 146A: 1530–1542
37. Quinzii C, Naini A, Salviati L et al. A mutation in para-hydroxybenzoate-
polyprenyl transferase (COQ2) causes primary coenzyme Q10 defi-
ciency. Am J Hum Genet 2006; 78: 345–349
38. Heeringa SF, Chernin G, Chaki M et al. COQ6 mutations in human
patients produce nephrotic syndrome with sensorineural deafness.
J Clin Invest 2011; 121: 2013–2024
39. Lopez LC, Schuelke M, Quinzii CM et al. Leigh syndrome with nephr-
opathy and CoQ10 deficiency due to decaprenyl diphosphate synthase
subunit 2 (PDSS2) mutations. Am J Hum Genet 2006; 79: 1125–1129
40. Buscher AK, Kranz B, Buscher R et al. Immunosuppression and renal
outcome in congenital and pediatric steroid-resistant nephrotic syn-
drome. Clin J Am Soc Nephrol 2010; 5: 2075–2084
41. Santin S, Bullich G, Tazon-Vega B et al. Clinical utility of genetic
testing in children and adults with steroid-resistant nephrotic syn-
drome. Clin J Am Soc Nephrol 2011; 6: 1139–1148
42. Santin S, Garcia-Maset R, Ruiz P et al. Nephrin mutations cause
childhood- and adult-onset focal segmental glomerulosclerosis.
Kidney Int 2009; 76: 1268–1276
43. Santin S, Tazon-Vega B, Silva I et al. Clinical value of NPHS2
analysis in early- and adult-onset steroid-resistant nephrotic syn-
drome. Clin J Am Soc Nephrol 2011; 6: 344–354
44. He N, Zahirieh A, Mei Y et al. Recessive NPHS2 (Podocin) mutations
are rare in adult-onset idiopathic focal segmental glomerulosclerosis.
Clin J Am Soc Nephrol 2007; 2: 31–37
45. Cho HY, Lee JH, Choi HJ et al. WT1 and NPHS2 mutations in
Korean children with steroid-resistant nephrotic syndrome. Pediatr
Nephrol 2008; 23: 63–70
46. Lowik M, Levtchenko E, Westra D et al. Bigenic heterozygosity and
the development of steroid-resistant focal segmental glomeruloscle-
rosis. Nephrol Dial Transplant 2008; 23: 3146–3151
47. Hinkes B, Vlangos C, Heeringa S et al. Specific podocin mutations
correlate with age of onset in steroid-resistant nephrotic syndrome.
J Am Soc Nephrol 2008; 19: 365–371
48. Machuca E, Hummel A, Nevo F et al. Clinical and epidemiological
assessment of steroid-resistant nephrotic syndrome associated with
the NPHS2 R229Q variant. Kidney Int 2009; 75: 727–735
49. Tonna SJ, Needham A, Polu K et al. NPHS2 variation in focal and
segmental glomerulosclerosis. BMC Nephrol 2008; 9: 13
50. Aucella F, De Bonis P, Gatta G et al. Molecular analysis of NPHS2
and ACTN4 genes in a series of 33 Italian patients affected by adult-
onset nonfamilial focal segmental glomerulosclerosis. Nephron Clin
Pract 2005; 99: c31–c36
51. Boyer O, Benoit G, Gribouval O et al. Mutational analysis of the
PLCE1 gene in steroid resistant nephrotic syndrome. J Med Genet
2010; 47: 445–452
52. Gbadegesin R, Bartkowiak B, Lavin PJ et al. Exclusion of homozy-
gous PLCE1 (NPHS3) mutations in 69 families with idiopathic and
hereditary FSGS. Pediatr Nephrol 2009; 24: 281–285
53. Benoit G, Machuca E, Nevo F et al. Analysis of recessive CD2AP and
ACTN4 mutations in steroid-resistant nephrotic syndrome. Pediatr
Nephrol 2010; 25: 445–451
Nephrol Dial Transplant (2012): Editorial Review
54. Gigante M, Pontrelli P, Montemurno E et al. CD2AP mutations are
associated with sporadic nephrotic syndrome and focal segmental
glomerulosclerosis (FSGS). Nephrol Dial Transplant 2009; 24:
1858–1864
55. Mucha B, Ozaltin F, Hinkes BG et al. Mutations in the Wilms’ tumor
1 gene cause isolated steroid resistant nephrotic syndrome and occur
in exons 8 and 9. Pediatr Res 2006; 59: 325–331
56. Santin S, Ars E, Rossetti S et al. TRPC6 mutational analysis in a large
cohort of patients with focal segmental glomerulosclerosis. Nephrol
Dial Transplant 2009; 24: 3089–3096
57. Gigante M, Caridi G, Montemurno E et al. TRPC6 mutations in
children with steroid-resistant nephrotic syndrome and a typical phe-
notype. Clin J Am Soc Nephrol 2011; 6: 1626–1634
58. Heeringa SF, Moller CC, Du J et al. A novel TRPC6 mutation that
causes childhood FSGS. PLoS One 2009; 4: e7771
59. Boyer O, Benoit G, Gribouval O et al. Mutations in INF2 are a major
cause of autosomal dominant focal segmental glomerulosclerosis.
J Am Soc Nephrol 2011; 22: 239–245
60. Franceschini N, North KE, Kopp JB et al. NPHS2 gene, nephrotic
syndrome and focal segmental glomerulosclerosis: a HuGE review.
Downloaded from http://ndt.oxfordjournals.org/ at University of Louisville on January 31, 2013
Genet Med 2006; 8: 63–75
61. Caridi G, Bertelli R, Di DM et al. Broadening the spectrum of diseases
related to podocin mutations. J Am Soc Nephrol 2003; 14: 1278–1286
62. Kottgen A, Hsu CC, Coresh J et al. The association of podocin R229Q
polymorphism with increased albuminuria or reduced estimated GFR
in a large population-based sample of US adults. Am J Kidney Dis
2008; 52: 868–875
63. Ruf RG, Lichtenberger A, Karle SM et al. Patients with mutations in
NPHS2 (podocin) do not respond to standard steroid treatment of
nephrotic syndrome. J Am Soc Nephrol 2004; 15: 722–732
64. KDIGO. Clinical practise guidelines for glomerulonephritis: treatment
of adult patients with idiopathic focal segmental glomerulosclerosis
(FSGS). Kidney Int Suppl 2011 (in press)
65. Faul C, Donnelly M, Merscher-Gomez S et al. The actin cytoskeleton
of kidney podocytes is a direct target of the antiproteinuric effect of
cyclosporine A. Nat Med 2008; 14: 931–938
66. Conlon PJ, Lynn K, Winn MP et al. Spectrum of disease in familial
focal and segmental glomerulosclerosis. Kidney Int 1999; 56:
1863–1871
67. Jungraithmayr TC, Hofer K, Cochat P et al. Screening for NPHS2
mutations may help predict FSGS recurrence after transplantation.
J Am Soc Nephrol 2011; 22: 579–585
68. Weber S, Gribouval O, Esquivel EL et al. NPHS2 mutation analysis
shows genetic heterogeneity of steroid-resistant nephrotic syndrome
and low post-transplant recurrence. Kidney Int 2004; 66: 571–579
69. Bertelli R, Ginevri F, Caridi G et al. Recurrence of focal segmental
glomerulosclerosis after renal transplantation in patients with muta-
tions of podocin. Am J Kidney Dis 2003; 41: 1314–1321
70. Benoit G, Machuca E, Antignac C. Hereditary nephrotic syndrome: a
systematic approach for genetic testing and a review of associated
podocyte gene mutations. Pediatr Nephrol 2010; 25: 1621–1632
71. Patrakka J, Ruotsalainen V, Reponen P et al. Recurrence of nephrotic
syndrome in kidney grafts of patients with congenital nephrotic syn-
drome of the Finnish type: role of nephrin. Transplantation 2002; 73:
394–403
72. Winn MP, Alkhunaizi AM, Bennett WM et al. Focal segmental
glomerulosclerosis: a need for caution in live-related renal transplan-
tation. Am J Kidney Dis 1999; 33: 970–974
Received for publication: 21.10.11; Accepted in revised form: 8.12.11